Pharmaceutical compositions and method of treating allergic conditions utilizing 2-nitroindane-1,3-dione derivatives as the active agents

ABSTRACT

Compositions containing 2-nitroindane-1,3-dione derivatives as active agents are useful in the prophylaxis and treatment of asthma, hayfever and also in the treatment of rhinitis.

This is a division of application Ser. No. 421,239, filed Dec. 3, 1973,and now U.S. Pat. No. 3,925,557 which is a division of Ser. No. 317,296,filed Dec. 21, 1972 and now U.S. Pat. No. 3,936,504.

This invention relates to pharmaceutical compositions which are usefulin the inhibition of the effects of certain types of antigen-antibodyreactions, and are therefore useful in the prophylaxis and treatment ofdiseases associated with allergic or immunological reactions, e.g.certain types of asthma and hay-fever, and also in the treatment ofrhinitis.

We have discovered that certain derivatives of 2-nitroindane-1,3-dionehave useful activity in warm-blooded mammals in that they inhibit theeffects of certain types of antigen-antibody reactions. In particular,they appear to inhibit the release of mediator substances, such ashistamine, which are normally released after antigen-antibodycombinations and which normally mediate the allergic response. The classof 2-nitroindane-1,3-dione derivatives which we have found to be activein this way has formula (I): ##SPC1##

and the salts of compounds (I) are also active. In formula (I), R₁, R₂,R₃, and R₄ are each hydrogen or alkyl, alkoxy, aryl, aralkyl,heterocyclic or halogen groups, or any two adjacent groups Rr₁ and R₂,R₂ and R₃, or R₃ and R₄ taken together represent the residue of asubstituted or unsubstituted carbocyclic or heterocyclic ring system.However, a search of the chemical literature has revealed that not allof the members of class (I) are novel compounds. Below we list thosecompounds of formula (I) which are mentioned in the literature, togetherwith the appropriate literature reference:

    ______________________________________                                        (I): R.sub.1 =R.sub.2 =R.sub.3 =R.sub.4 =H                                    (I): R.sub.1 =R.sub.2 =OCH.sub.3 ; R.sub.3 =R.sub.4 =H                                         Chem.Abs. 1961, 55, 476g                                     (I): R.sub.2 =OCH.sub.3 ; R.sub.1 =R.sub.3 =R.sub.4 =H                                         Chem.Abs. 1968, 68, 87034q                                   (I): R.sub.1 =Cl; R.sub.2 =R.sub.3 =R.sub.4 =H                                                 Chem.Abs. 1969, 70, 11379b                                   (I): R.sub.2 =Cl; R.sub.1 =R.sub.3 =R.sub.4 =H                                                 Chem.Abs. 1969, 70, 37507s                                   (I): R.sub.2 =Br; R.sub.1 =R.sub.3 =R.sub.4 =H                                                 Chem.Abs. 1972, 132349s                                      (I): R.sub.1 =CH.sub.3 ; R.sub.2 =R.sub.3 =R.sub.4 =H                                          Latv. PSR Zinat Akad, Vestis                                                  (Khim Ser) 1971, 425-30                                      (I): R.sub.2 =I; R.sub.1 =R.sub.3 =R.sub.4 =H                                                  ibid 1971, 179-181                                           ______________________________________                                    

In the above list, no reference has been given for the first compound,i.e. 2-nitroindane-1,3-dione itself which is, of course, a commonlaboratory reagent.

Although the above compounds are reported in the literature, no form ofuseful biological activity has been ascribed to them. Likewise there hasbeen in the literature no suggestion that such compounds are likely topossess any form of useful biological activity, and in particular thediscovery that they have anti-allergic activity has not been predictedin any way.

Accordingly, the present invention provides in its broadest aspect, apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt thereof: ##SPC2##

together with one or more pharmaceutically acceptable carriers, in whichformula R₁, R₂, R₃ and R₄ represent hydrogen, lower alkyl, lower alkoxy,aryl, aralkyl, heterocyclic or halogen groups, and any two adjacentgroups R₁ and R₂, R₂ and R₃ or R₃ and R₄ may be joined in a carbocyclicor heterocyclic ring system, this definition of R₁, R₂, R₃ and R₄ beingsubject to the proviso that R₁, R₂, R₃ and R₄ are not simultaneouslyhydrogen.

It will be noted that the above definition of the compositions of thisinvention specifically excludes compositions 2-nitroindane-1,3-dioneitself. This exclusion is necessary since such compositions are claimedin a different pending patent application commonly assigned.

The compositions of this invention may be presented as a microfinepowder for insufflation, e.g. as a snuff or in capsules of hardgelatine. They may also be presented together with a sterile liquidcarrier for injection. Some of the compounds of formula (I) appear to beactive when given by the oral route and thus the compositions of thisinvention may be in the form of tablets, capsules, pills or syrups.Preferably the compositions of this invention are presented in unitdosage form, or in a form in which the patient can administer to himselfa single dosage. If desired, a small amount of bronchodilator compoundmay be incorporated in the compositions of the invention, both toinhibit the cough response if the composition is insufflated and toprovide immediate relief during an asthmatic attack. The effective doseof compound (I) depends on the particular compound employed, but isgenerally in the range of from 0.1 mg/kg/day to 100 mg/kg/day.

The precise nature of the pharmaceutical carrier used in the compositionof this invention is not important. Standard pharmaceutical practice maybe followed, but it is perhaps worth noting that if the composition isto be administered by insufflation, a microfine powder wheresubstantially all the particles have diameters of less than 50 micronsis preferred.

The present invention also provides, in another of its aspects compoundsof formula (I) and salts thereof: ##SPC3##

wherein R₁, R₂, R₃ and R₄ are each hydrogen or alkyl, alkoxy, aryl,aralkyl, heterocyclic or halogen groups, or any two adjacent groups, R₁and R₂, R₂ and R₃, R₃ and R₄ may be joined in a carbocyclic orheterocyclic ring system, with the exception of the following compoundsand salts thereof:

2-nitroindane-1,3-dione

4,5-dimethoxy-2-nitiroindane-1,3-dione

5-methoxy-2-nitroindane-1,3-dione

4-chloro-2-nitroindane-1,3-dione

5-chloro-2-nitroindane-1,3-dione

5-bromo-2-nitroindane-1,3-dione

4-methyl-2-nitroindane-1,3-dione

5-iodo-2-nitroindane-1,3-dione

Hereafter in this specification when the phrase "the compounds of thisinvention" is used, it is to be understood that we mean compounds offormula (I) and salts thereof excluding the eight compounds specificallylisted above, and their salts.

Examples of groups R₁, R₂, R₃ and R₄ which may be present in thecompounds of this invention include methyl, ethyl, n- and iso- propyl,n-, sec- and tert- butyl; methoxy, ethoxy, n- and iso- propoxy, n-, sec-and tert- butoxy, phenyl, benzyl, pyridyl, fluoro, chloro, bromo or iodogroups. In addition R₁ and R₂ or R₂ and R₃ and R₄ taken together mayrepresent the residue of a 1,2-phenylene or 1,2-cyclohexylene ring,which may carry one or more of the substituents listed above.

Compounds of the present invention which are especially preferred fortheir high activity include the following compounds and theirpharmaceutically acceptable salts:

5,6-dimethyl-2-nitroindane-1,3-dione;

2-nitrobenz[f]indane-1,3-dione;

4-methoxy-6-ethyl-2-nitroindane-1,3-dione;

4-n-butoxy-2-nitroindane-1,3-dione;

4,6-dimethyl-2-nitroindane-1,3-dione; acid)

5-methyl-2-nitroindane-1,3-dione;

4-fluoro-2-nitroindane-1,3-dione;

In the preceeding paragraphs, we have referred to pharmaceuticallyacceptable salts of the compounds of formula (I). Such salts include thealkali metal salts e.g. sodium or potassium, and salts with organicbases such as amines or amino compounds. These compounds may, onoccasions, be capable of existing in an anhydrous form or one or morehydrates. The invention includes all of these forms.

The compounds of this invention may be prepared by a process whichcomprises nitrating the parent indane-1,3-dione of formula (III):##SPC4##

wherein R₁, R₂, R₃ and R₄ are as hereinbefore defined. The nitrationstep may be carried out at various temperatures although usually below25°C. In general a temperature range of from -20°C to +20°C will besuitable, with +10°C being preferred.

The starting materials of formula (III) above may be prepared by knownmethods, the choice of method being dependent on the nature of thesubstituents present. With a single relatively chemically inertsubstituent such as a methyl, methoxy, or phenyl radical, the method ofchoice is the Claisen condensation wherein a compound of formula (IV):##SPC5##

wherein R is the inert substituent and X is an alkyl group is reactedwith ethyl acetate.

With alkyl or alkoxy substituents in both the 3- and 6- position of (IV)the Claisen condensation may sometimes afford only low yields of therequired diones and the same is true for the 4,5-methylenedioxyanalogue. In such cases the preferred method involves the reaction of acompound formula (V), formed from the appropriate anhydride and aceticanhydride. ##SPC6##

wherein both R₁ and R₂ are 4- or 7- alkyl or alkoxy groups or R₁ R₂ is a5,6-methylenedioxy group with a strong base such as sodium methoxide.

Neither of the above procedures is advisable in the presence of halogenfunctions, and here the Knoevenagel reaction is best suited. Thisinvolves the reaction of an active methylene compound with a compound offormula (VI): ##SPC7##

wherein Rr₁, R₂, R₃ and R₄ are the same or different and each ishydrogen or a halogen group. The use of ethyl acetoacetate as the activemethylene compound is most convenient (and economical) but has led todifficulties with both the 4-bromo and tetrachloro compounds, in whichthe carbethoxy intermediates are isolated ( (VII) and (VIII)respectively) ##SPC8##

For this reason, ethyl acetoacetate has been replaced by the more easilyremovable t- butyl acetoacetate with complete success.

The following Examples illustrate the preparation of some of thecompounds of this invention (and also a few of the previously knowncompounds listed above) and illustrate the biological activity of suchcompounds.

EXAMPLE 1 a. 4-Methyl indane-1,3-dione

To a 50% dispersion of sodium hydride in mineral oil (8.2 g; 0.17 moleof NaH) was added a solution of diethyl 3-methyl phthalate (28 g; 0.119mole) in ethyl acetate (40 ml) and the mixture refluxed with occasionalswirling on a steam bath for 4 hr. After cooling, the bright yellowsodium salt was filtered and washed with a little cold ethyl acetate. Tothe dried sodium salt (ca 27.2 g) was added rapidly a hot (80°C)solution of hydrochloric acid (48 ml) in water (480 ml) and the productkept at 70°C until decarboxylation ceased (7 mins), cooled to 5°C, andthe pale yellow solid filtered and washed with water. Recrystallisationfrom benzene afforded a pale yellow crystalline solid, m.p. 125°-8°C.(Found; C, 75.38; H, 5.04; C₁₀ H₈ O₂ requires; C, 74.99; H, 5.03%).

b. 4-Methyl-2-nitroindane-1,3-dione

To a stirred suspension of 4-methyl-1,3-indane-dione (1.02 g. 0.006mole) in anhydrous ether (5 ml) at ca 10°C was added dropwise and withstirring fuming nitric acid (2.0 ml). After 10 mins. a clear, darksolution formed followed by precipitation of a bright yellow N The masswas filtered and washed with 5N. hydrochloric acid. Recrystallizationfrom water/hydrochloric acid afforded the title compound, m.p. 108°-9°C.(Found; C, 56.16; H, 3.74; N, 6.32; C₁₀ H₇ NO₄.¹ /2H₂ O requires; C,56.07; H, 3.76; N, 6.54%).

EXAMPLE 2 a. 5-Methyl indane-1,3-dione

This was prepared as in Example 1(a) from diethyl 4-methyl phthalate,m.p. (benzene) 114°-116°C. (Found: C, 75.04; H, 5.19; C₁₀ H₈ O₂requires; C, 74.99; H, 5.03%).

b. 5-Methyl-2-nitroindane-1,3-dione

Nitration of 5-methyl indane-1,3-dione as in Example 1(b) yielded thenitro product, m.p. (water/hydrochloric cid) 115°-117°C. (Found; C,58.43; H, 3.39; N, 6.86; C₁₀ H₇ NO₄ requires; C, 58.54; H, 3.44; N,6.83%).

EXAMPLE 3 a. 4-Methoxy indane-1,3-dione

Dimethyl-3-methoxy phthalate (13.8 g; 0.062 mole) in ethyl acetate (20ml) was added to a 50% dispersion of sodium hydride in mineral oil (4.1g; 0.085 mole of NaH) and the mixture refluxed for 4 hr. in a waterbath. After cooling the red oil was treated with water and the yellowsolid filtered and washed well with cold water. The sodium salt (15.8 g)was decarboxylated with 5N hydrochloric acid (23 ml) at 70°C. M.p.(benzene) 145°-147°C (d). (Found; C, 68.22; H, 4.63; C₁₀ H₈ O₃ requires;C, 68.18; H, 4.58%).

b. 4-Methoxy-2-nitro indane-1,3-dione

Nitration of 4-methoxy indane-1,3-dione as in Example 1(b) afforded thetitle compound, m.p. (water, hydrochloric acid) 132°-4°C. (Found; C,54.39; H, 3.22; N, 6.42; C₁₀ H₇ NO₅ requires; C, 54.31; H, 3.19; N,6.33%).

EXAMPLE 4 a. 4-Ethoxy indane-1,3-dione

Dimethyl 3-ethoxy phthalate (m.p. 58°C) was converted into 4-ethoxyindane-1,3-dione according to Example 1(a), m.p. (benzene) 111°C.(Found; C, 69.48; H, 5.34; C₁₁ H₁₀ O₃ requires; C, 69.46; H, 5.30%).

b. 4-Ethoxy-2-nitro indane-1,3-dione

Direct nitration of 4-ethoxy indane-1,3-dione with fuming nitric acid asin Example 1(b) gave the 2-nitro derivative, m.p. (water, hydrochloricacid) 95°-96°C. (Found; C, 48.83; H, 4.81; N, 4.97; C₁₀ H₉ NO₅. 2H₂ Orequires; C, 48.71; H, 4.83; N, 5.17%).

EXAMPLE 5 a. Benz[f] indane-1,3-dione

This was preparead by an analagous procedure to that described inExample 1(a), m.p. 136°C (d) from benzene. (Found; C, 73.80; H, 4.15;C₁₃ H₈ O₂.H₂ O requires; C, 72.89; H, 4.71%).

b. 2-Nitro benz[f] indane-1,3-dione

Nitration of benz[f] indane-1,3-dione with fuming nitric acid in etherat 10°C afforded the title compound, m.p. (water, hydrochloric acid)163°-4°C. (Found; C, 64.89; H, 3.06; N, 5.03; C₁₃ H₇ NO₄ requires; C,64.74; H, 2.93; N, 5.81%).

EXAMPLE 6 a. 3-Methoxy-6-methyl phthalalyl acetic acid

3-Methoxy-6-methyl phthalic anhydride (21.29 g; 0.11 mole) was treatedwith freshly fused potassium acetate (16.7 g) and acetic anhydride (35ml). The resulting mixture was heated for 1 hr. at 100°C and then for afurther 4 hrs. at 150°-5°C. After cooling water (100 ml) was added andthe dark precipitate filtered and washed well with cold water andmethanol until the filtrate was almost colourless; the solid wasextracted with 5% aqueous sodium bicarbonate (500ml) and the filteredextract acidified. A pale yellow precipitate of the phthalalylaceticacid separated in quantitative m.p. (dioxan) 260°-2°C (d). (Found; C,61.13; H, 4.40; C₁₂ H₁₀ O₅ requires; C, 61.54; H, 4.30%).

b. 4-Methoxy-7-methyl indane-1,3-dione

Sodium methoxide [from sodium (10.8 g)] in methanol (100 ml) was addedwith vigorous shaking to a solution of 3-methoxy-6-methyl phthalalylacetic acid (10.8 g; 0.046 mole) in methanol (250 ml) and the mixturestood at ambient temperature for 2 hrs. The resulting orange gel washeated for 5 hrs. at 100°C, cooled and then filtered. On addition of hot(80°C) 5N hydrochloric acid (160 ml) spontaneous decarboxylation ensuedand an orange-yellow solid formed. Filtration and recrystallisation(benzene) afforded the indanedione, m.p. 172°C as a buff solid. (Found;C, 69.50; H, 5.34; C₁₁ H₁₀ O₃ requires; C, 69.46; H, 5.30%).

c. 4-Methoxy-7-methyl-2-nitro indane-1,3-dione

Treatment of 4-methoxy-7-methyl indane-1,3-dione with fuming nitric acidas in Example 1(b) gave the 2-nitro derivative as a yellow solid, m.p.(water, hydrochloric acid) 143°-146°C. (Found; C, 56.61; N, 3.93; N,5.80; C₁₁ H₉ NO₅ requires; C, 56.18; H, 3.86; N, 5.96%).

EXAMPLE 7 a. 5-Bromo indane-1,3-dione

A solution of 4-bromo phthalic anhydride (4.15 g; 0.018 mole) in aceticanhydride (10 g) containing triethylamine (4 g) was treated at roomtemperature with ethyl acetoacetate (2.38 g; 0.02 mole). After 24 hrs.with stirring, crushed ice (20 g) and concentrated hydrochloric acid (10ml) were added and the precipitated red solid filtered. Addition of ahot (70°-80°C) solution of hydrochloric acid (150 ml) in water (750 ml)to this solid resulted in decarboxylation and generation of 5-bromoindane-1,3-dione as red plates, m.p. (acetone) 152°-3°C. (Found; C,48.04; H, 2.17; Br, 35.63; C₉ H₅ Br O₂ requires; C, 48.05; H, 2.24; Br,35.52%).

b. 5-Bromo-2-nitro indane-1,3-dione

Nitration as described in Example 1(b) converted 5-bromoindane-1,3-dione to itis 2-nitro derivative, m.p. (water, hydrochloricacid) 127°-9°C. (Found; C, 40.03; H, 1.55; N, 5.11, Br, 29.32; C₉ H₄ BrNO₄ requires; C, 40.01, H, 1.49; N, 5.18; Br, 29.58%).

EXAMPLE 8

a. 4-Bromo indane-1,3-dione

A modification of the procedure used in Example 7(a) in which ethylacetoacetate was replaced by t-butyl acetoacetate afforded 4-bromoindane-1,3-dione from the anhydride, decomposes above 120°C.

b. 4-Bromo-2-nitro indane-1,3-dione

This was prepared as for the 5-bromo isomer m.p. (water, hydrochloricacid) 127°-8°C. (Found; C, 40.16; H, 1.60; N, 5.36; Br, 28.65; C₉ H₄ BrNO₄ requirements; C, 40.01; H, 1.49; N, 5.18; Br, 29.58%).

EXAMPLE 9

a. 4-Fluoro indane-1,3-dione

Using the procedure outlined in Example 8(a) gave 4-fluoroindane-1,3-dione m.p. (benzene) 117°-118°C from 4-fluoro phthalicanhydride. (Found; C, 65.87; H, 3.15; C₉ H₅ FO₂ requires; C, 65.86; H,3.07%).

b. 4-Fluoro-2-nitro indane-1,3-dione

The title compound was formed by nitration of 4-fluoro indane-1,3-dioneat 10°C, m.p. (water, hydrochloric acid) 124°C. (Found; C, 47.75; H,2.68; N, 6.19; C₉ H₄ F NO₄.H₂ O requires; C, 47.59; H, 2.66; N, 6.17%).

EXAMPLE 10

a. 4,5,6,7-Tetrachloro indane-1,3-dione

Tetrachloro phthalic anhydride was converted to the indane dione by themethod described in Example 8(a), decomposes on heating. (Found; C,39.01; H, 0.75; Cl, 50.15; C₉ H₂ Cl₄ O₂ requires: C, 38.07; H, 0.71; C,49.60%).

b. 2-Nitro-4,5,6,7-tetrachloro indane-1,3-dione

Nitration of 4,5,6,7-Tetrachloro indane-1,3-dione at 10°C afforded the2-nitro derivative, m.p. (water, hydrochloric acid) 184°-5°C. (Found; C,27.89; H, 1.40; N, 3.41; C₉ H Cl₄ NO₄.3H₂ O requires; C, 28.22; H, 1.84;N, 3.66%).

EXAMPLE 11

a. Dimethyl 3,6-dihydro-4,5-dimethyl phthalate

2,3-dimethyl butadiene (30 g; 0.366 mole) and dimethyl acetylenedicarboxylate 47.69 0.366 mole) were heated to 140°C in an autoclave andmaintained at the temperature for 4 hrs. After cooling ether was addedand the solution filtered. Evaporation of the filtrate afforded thetitle compound which was recrystallised from methanol; light petroleum(40-60), m.p. 71°-72°C (Found; C, 64.41; H, 7.16; C₁₂ H₁₆ O₄ requires;C, 64.27; H, 7.19%).

b. Dimethyl 4,5-dimethyl phthalate

The above dihydro aromatic compound (50 g.) was added to 10% palladiumon charcoal (2.5 g.) and the mixiture aerated at 220°-225°C for 3 hrs.After cooling ether was added and the mixture filtered. Evaporation anddistillation afforded dimethyl 4,5-dimethyl phthalate, m.p. (methanol,light petroleum (40-60)) 53°-4°C. (Found: C, 64.87; H, 6.36; C₁₂ H₁₄ O₄requires: C, 64.85; H, 6.35%).

c. 5,6-Dimethyl indane-1,3-dione

Dimethyl 4,5-dimethyl phthalate (14.6 g; 0.066 mole) in ethyl acetate(20 ml.) was added to a 50% dispersion of sodium hydride in mineral oil(4.63 g; 0.096 mole of NaH) and the mixture refluxed for 4 hrs. on asteam bath. After cooling the yellow solid was filtered and washed witha little cold ethyl acetate. Treatment with a hot (80°C) solution ofconcentrated hydrochloric acid (20 ml.) in water (200 ml.) for 7 mins.gave the title compound. m.p. (benzene) 159°C. (Found: C, 75.77; H,5.79; C₁₁ H₁₀ O requires: C, 75.84; H, 5.79%).

d. 5,6-Dimethyl-2-nitro-indane-1,3-dione

5,6-dimethyl indane-1,3-dione (0.52 g; 0.003 mole) suspended inanhydrous ether (5 ml.) was stirred at 10°C during the dropwise additionof fuming nitric acid (1.0 ml.). After the addition was complete themixture was stirred at ambient temperature for 1 hr. and theprecipitated yellow solid filtered. m.p. (water, hydrochloric acid)111°-113°C. (Found: C, 60.11; H, 4.10; N, 6.14; C₁₁ H₉ NO₄ requires: C,60.28; H, 4.14; N, 6.39%).

EXAMPLE 12

a. 4-Isopropyloxy indane-1,3-dione

Dimethyl 3-isopropyloxy phthalate (41.93 g; 0.166 mole) in ethyl acetate(55 ml) was cautiously added to a 50% dispersion of sodium hydride inmineral oil (11.0 g; 0.228 mole of NaH) and the mixture refluxed for 4hours on a steam bath. A yellow solid separated which, after cooling,was filtered and washed with a little ethyl acetate. Addition of thissolid to 1N hydrochloric acid at 80°C caused immediate decarboxylationwhich was complete within 10.15 mins.

After cooling and filtration, recrystallisation (benzene, petroleum(40°- ) afforded the title product, m.p. 69°-70°C (Found: C, 70.88; H,5.93; C₁₂ H₁₂ O₂ requires: C, 70.58; H, 5.92%).

b. 4-Isopropyloxy-2-nitro-indane-1,3-dione

4-Isopropyloxy indane-1,3-dione (0.16 g; 0.003 mole) suspended in dryether (5 ml) was treated dropwise and with stirring with fuming nitricacid (1.0 ml) at 10°C. The resulting dark solution was treated with 5Nhydrochloric acid and evaporated to a yellow crystalline product; m.p.(water, hydrochloric acid) 80°-81°C. (Found: C, 57.94; H, 4.43; N, 5.46;C₁₂ H₁₁ NO₅ requires: C, 57.83; H, 4.45; N, 5.62%).

EXAMPLE 13

a. 4,6-Dimethyl indane-1,3-dione

Dimethyl 3,5-dimethyl phthalate (15.1 g; 0.068 mole) in ethyl acetate(22 ml.) was treated with a 50% dispersion of sodium hydride in mineraloil (4.80 g; 0.10 mole of NaH) and the mixture refluxed for 4 hrs. at100°C. After filtration the resulting yellow sodium salt was treated for7 mins. at 70°-80°C. with hydrochloric acid (11.0 ml.) in water (110ml.) and the dione product filtered and recrystallised. m.p. (benzene)137°-138°C. (Found: C, 75.73; H, 5.67; C₁₁ H₁₀ O₂ requires: C, 75.84; H,5.79%).

b. 4,6-Dimethyl-2-nitro-indane-1,3-dione

4,6-Dimethyl indane-1,3-dione (0.52 g; 0.003 mole) suspended inanhydrous ether (5 ml.) was nitrated to the title product as describedin Example 12 m.p. (water, hydrochloric acid) 111°-112°C, (Found: C,60.12, H, 4.16; N, 6.14; C₁₁ H₉ NO₄ requires: C, 60.28; H, 4.14; N,6.39%).

EXAMPLE 14

a. Benz (e) indane-1,3-dione

To a 50% dispersion of sodium hydride in mineral oil (4.55 g) was addedto a solution of diethyl naphthalene 1,2-dicarboxylate (18.5 g) in ethylacetate (22 ml.) and the mixture refluxed for 3.5 hrs. on a steam bath.After cooling the precipitated orange solid was filtered anddecarboxylated with hydrochloric acid (35 ml.) in water (350 ml) at 70°Cover 7 mins. to yield benze(e) indane-1,3-dione, m.p. (benzene) 178°C(decomp.) (Found: C, 79.21; H, 4.22; C₁₃ H₈ O₂ requires: C, 79.58; H,4.11%).

b. 2-Nitro benze(e)indane-1,3-dione

Nitration of benz(e) indane-1,3-dione as described in Example 12afforded the 2-nitro derivative as an orange crystalline solid, m.p.(water, hydrochloric acid) 134.5°-135.5°C. (Found: C, 64.76; H, 2.91; N,5.59; C₁₃ H₇ NO₄ requires: C, 64.74; H, 2.93; N, 5.81%).

EXAMPLE 15

a. 3,6-Dimethyl phthalalyl acetic acid

3,6-Dimethyl phthalic anhydride (m.p. 144°-5°C; 15.3 g; 0.087 mole) wastreated with freshly fused potassium acetate (13.3 g) and aceticanhydride (27 ml) and heated at 100°C for 1 hr. The mixture was thenheated to 150°-155°C at which temperature it was maintained for 4 hours.After cooling, water (80 ml) was added and the brown solid filtered offand washed well with water and cold methanol, After extraction of theresidue with 5% sodium bicarbonate followed by acidification of theextract, the title compound was isolated as a yellow solid, m.p.(dioxan) 264°-5°C (Found: C, 66.04; H, 4.69; C₁₂ H₁₀ O₄ requires: C,66.05; H, 4.62%).

b. 4,7-Dimethyl indane-1,3-dione

Sodium methoxide (from sodium 8.05 g in methanol (80 ml)) was added withvigorous stirring to a solution of 3,6-dimethyl phthalalyl acetic acid(7.5 g) in methanol (200 ml) and the gel allowed to stand for 2 hrs. Thered suspension was then refluxed for 5 hours on a steam bath, cooled andfiltered. Addition of the solid to hot (80°C) 5N hydrochloric acid (120ml) caused immediate decarboxylation and generation of the dione. Aftercooling the indane dione was filtered, dried, recrystallised, m.p.(benzene) 187°-188°C (Found: C, 75.48; H, 5.88; C₁₁ H₁₀ O₂ requires: C,75.84; H, 5.79%).

c. 4,7-Dimethyl-2-nitro-indane-1,3-dione

4,7-Dimethyl indane-1,3-dione (0.52 g; 0.003 mole) in dry ether (5 ml)was nitrated with fuming nitric acid (1.0 ml) as described in Example 12to give 4,7-dimethyl-2-nitro-indane-1,3-dione, m.p. (water, hydrochloricacid) 108°-110°C, (Found: C, 60.07; H, 4.20; N, 6.29; C₁₁ H₉ NO₄requires: C, 60.28; H, 4.14; N, 6.39%).

EXAMPLE 16 a. Dimethyl-3-ethyl phthalate

Dimethyl acetylene dicarboxylate (26.0 g; 0.183 mole) was added to asolution of 1,3-hexadine (15.0 g; 0.183 mole) in dry benzene (100 ml)and the mixture stirred in an autoclave at 65°C for 24 hours.Evaporation and distillation then afforded the dihydro aromatic adductas a colourless oil, bp₀.3 mm Hg. 80°-100°C. Aeration of this at220°-225°C in the presence of 10% palladinised charcoal over 3 hoursthen afforded, after spinning bend separation, the title compound as acolourless oil bp₁.2 mm Hg. 126°C; (Found: 64.46; H, 6.46; C₁₂ H₁₄ O₄requires: C, 64.85; H, 6.35%).

b. 4-Ethyl indane-1,3-dione

A solution of dimethyl 3-ethyl phthalate (7.38 g; 0.033 mole) in ethylacetate (10 ml) was added to a 50% dispersion of sodium hydride inmineral oil (2.32 g) and the mixture refluxed for 4 hours on a steambath. After cooling the yellow sodium salt was filtered, washed wellwith dry ether and dried. Treatment with a hot (80°C) solution ofhydrochloric acid (10 ml) in water (100 ml) over 10 mins. then gave therequisite dione; m.p. (benzene) 148°C; (Found: C, 76.65; H, 5.45; C₁₁H₁₀ O₂ requires: C, 75.85; H, 5.80%).

c. 4-Ethyl-2-nitro indane-1,3-dione

A suspension of 4-ethyl indane-1,3-dione (0.52 g; 0.003 mole) in dryether (5 ml) was treated dropwise at 10°C with fuming nitric acid (1.0ml) and the precipitated product filtered after 40 mins. at roomtemperature; m.p. (water, hydrochloric acid) 98°-100°C; (Found; C,59.98; H, 4.18; N, 6.34; C₁₁ H₉ NO₄ requires: C, 60.28; H, 4.14; N,6.39%).

EXAMPLE 17 a. 4-Methoxy-6indane-indane11,3-dione

Dimethyl 3-methoxy-5-methyl phthalate (14.8 g: 0.062 mole) in ethylacetate (20 ml) was added to a 50% dispersion of sodium hydride inmineral oil (4.1 g; 0.085 mole) and the mixture refluxed for 4 hours at100°C. Addition of ether, ethyl acetate to the residual cooled oilafforded a yellow solid which was filtered. Treatment of this solid with5N hydrochloric acid (30 ml) at 70°C during 7 mins. afforded the titleproduct m.p. (benzene) 172°-3°C (Found: C, 69.45; H, 5.43; C₁₁ H₁₀ O₃requires; C, 69.46; H, 5.30%).

b. 4-Methoxy-6-methyl-2-nitro indane-1,3-dione

A suspension of 4-methoxy-6-methyl indane-1,3-dione in dry ether wasnitrated as in Example 16(c) to yield the 2-nitro derivative; m.p.(water, hydrochloric acid) 156°-57°C. (Found: C, 56.00; H, 3.86; N,5.90; C₁₁ H₉ NO₅ requires: C, 56.16; H, 3.86; N, 5.96%).

EXAMPLE 18 a. 6-Ethyl-4-methoxy indane-1,3-dione

Claisen condensation of dimethyl 5-ethyl-3-methoxy phthalate (m.p. 89°C)as given in Example 16 (b) afforded the title product m.p. (benzene,petroleum [40°-60°C]) 112°-113°C. (Found: C, 70.60; H, 5.97; C₁₂ H₁₂ O₃requires; C, 70.57; H, 5.92%).

b. 6-Ethyl-4-methoxy-2-nitro indane-1,3-dione

Nitration of a suspension of 6-ethyl-4-methoxy indane-1,3-dione in dryether as described in Example 16(c) gave the 2-nitro derivative, m.p.(water, hydrochloric acid) 116°C; (Found: C, 57.85; H, 4.47; N, 5.77;C₁₂ H₁₁ NO₅ requires: C, 57.83; H, 4.45; N, 5.62%).

EXAMPLE 19

a. 5-Phenyl indane-1,3-dione

A solution of dimethyl 4-phenyl phthalate (bp 0.1 170°-80°C) in ethylacetate was cyclised to the indane dione as described in Example 16(b),m.p. (benzene, petroleum [40°-60°]) 116°C. (Found: C, 80.96; H, 4.70;C₁₅ H₁₀ O₂ requires: C, 81.07; H, 4.54%).

b. 2-Nitro-5-phenyl indane-1,3-dione

Nitration of 5-phenyl indane-1,3-dione with fuming nitric acid asdescribed in Example 16 (c) gave 2-nitro-5-phenyl indane-1,3-dione, m.p.(water, hydrochloric acid) 119°C. (Found: C, 65.54; H, 3.39; N, 4.93;C₁₅ H₉ NO₄. 1/2 H₂ O requires: C, 65.21; H, 3.65; N, 5.07%).

EXAMPLE 20

a. 4-Isobutyloxy indane-1,3-dione

A solution of dimethyl 3isobutyloxy phthalate (26.6 g; 0.1 mole; b.p.₀.1mm Hg 140°-144°C in ethyl acetate (34 ml) was treated with a 50%dispersion of sodium hydride in mineral oil (6.64 g; 0.137 mole) and thebrown solution refluxed for 4 hours on a steam bath. The bright yellowsolid which separated was filtered and cleaned by trituration withethanol:ether (3:1). Decarboxylation with 5N hydrochloric acid (45 ml)at 70°C over 10 min. gave the title dione; m.p. (benzene, petroleum[40°-60°]) 65°C. (Found: C, 71.63; H, 6.52; C₁₃ H₁₄ O₄ requires: C,71.54; H, 6.47%).

b. 4-Isobutyloxy-2-nitro indane-1,3-dione

4-Isobutyloxy indane-1,3-dione (0.654 g; 0.003 mole) suspended in dryether (5 ml) was treated dropwise with fuming nitric acid (1.0 ml) at10°C and the clear dark red solution left to stir at room temperaturefor 1 hour. Evaporation in the presence of 5N hydrochloric acid gave the2-nitro derivative as a yellow solid, m.p. (water, hydrochloric acid)75°-77°C. (Found: C, 58.92; H, 5.00; N, 5.48; C₁₃ H₁₃ NO₅ requires: C,59.31; H, 4.98; N, 5.32%).

EXAMPLE 21

a. 4-n-Butyloxy indane-1,3-dione

Claisen condensation of dimethyl 3-n-butyloxy phthalate (m.p. 48°C) withethyl acetate as described in Example 16 (b) afforded the titlecompound, m.p. (benzene, petroleum [40°-60°]) 66°C. (Found: C, 71.41; H,6.54; C₁₃ H₁₄ O₄ requires: C, 71.54; H, 6.47%).

b. 4-n-Butyloxy-2-nitro indane-1,3-dione

Nitration of 4-n-butyloxy indane-1,3-dione as described in Example 20(b)afforded the 2-nitro derivative, m.p. (water, hydrochloric acid) 85°C.(Found: C, 59.07; H, 5.13; N, 5.13; C₁₃ H₁₃ NO₅ requires: C, 59.31; H,4.98; N, 5.32%).

EXAMPLE 22

a. 4-n-Propyloxy indane-1,3-dione

Claisen condensation of dimethyl 3-n-propyloxy phthalate with ethylacetate as described in Example 20 (a) afforded 4-n-propyloxyindane-1,3-dione, m.p. (benzene) 94°-95°C. (Found: C, 70.69; H, 6.05;C₁₂ H₁₂ O₃ requires: C, 70.58; H, 5.92%).

b. 2-Nitro-4-n-Propyloxy indane-1,3-dione

Nitration of 4-n-Propyloxy indane-1,3-dione as described in Example 16(c) gave the 2-nitro derivative, m.p. (water, hydrochloric acid)114°-115°C. (Found: C, 57.57; H, 4.43; N, 5.48; C₁₂ H₁₁ NO₅ requires: C,57.83; H, 4.45; N, 5.62%).

EXAMPLE 23

a. 4-Phenyl indane-1,3-dione

Dimethyl 3-phenyl phthalate (15.0 g; 0.055 mole) in ethyl acetate (20ml) was added to a 50% dispersion of sodium hydride in mineral oil(3.67g) and the mixture refluxed for 4 hrs. on a steam bath. Separationof the bright yellow solid followed by decarboxylation with a hot (80°C)solution of hydrochloric acid (25 ml) in water (250 ml) over 7 mins.gave the title product, m.p. (benzene) 125°-128°C (Found: C, 80.94; H,4.69; C₁₅ H₁₀ O₂ requires: C, 81-07; H, 4.54%).

b. 2-Nitro-4-Phenyl indane-1,3-dione

Nitration of 4-phenyl indane-1,3-dione as described in Example 16 (c)afforded the 2-nitro derivative, m.p. (water, hydrochloric acid) 119°C;(Found: C, 67.04; H, 3.37; N, 4.96; C₁₅ H₉ NO₄ requires: C, 67.42; H,3.39; N, 5.24%).

EXAMPLE 24 BIOLOGICAL RESULTS

All of the 2-nitro indane-1,3-dione prepared in the preceding Exampleswere submitted for biological testing. The test system was the RatPassive Cutaneous Anaphylaxis (PCA) test described below in (ii).

(i) Serum containing heat labile homocytotropic antibody was raised inrats by a method similar to that used by Mota. (I. Mota Immunology 1964,7, 681).

Male Wistar rats of 250-300 g, were injected intraperitoneally with 0.5ml of Bordatella pertussis vaccine (containing 4 = 10¹⁰ dead organismper ml) and subcutaneously with 0.5 ml of an emulsion of 100 mg. ofovalbumin in 2 ml of saline and 3 ml of incomplete Freunds' adjuvant.Rats were bled by cardiac puncture on day 18, the blood was pooled andseparated and serum stored at -20° and thawed only once before use.

(ii) The P.C.A. test was similar to that described by Ovary and Bier (A.Ovary and O. E. Bier, Proc. Soc. Exp. Biol. Med. 1952, 81, 584) andGoose and Blair (J. Goose and A. M. J. N Blair, Immunology 1969, 16,769).

0.1 ml of each of six twofold serial dilutions of the serum in 0.9%saline were injected intradermally into separate sites on the shaveddorsal surface of 250-350 g. Wistar rats. 72 hours later the animalswere challenged by i.v. injection of 0.3 ml of 1% ovalbumin mixed with0.1 ml of a 5% solution of pontamine sky blue dye both in isotonicsaline buffered with pH. 7.2 Sorenson buffer (P.B.S.). The rats werekilled after 20 minutes and the diameter of of the blue wheals at theantibody injection sites were measured. The starting dilution of theserum was adjusted so that there was no response, after challenge, atthe site of injection of the highest dilution and a maximum response atthe lowest dilution. Typically, six twofold serial dilutions of theserum from 1/4 to 1/128 were used.

Compounds were tested for their ability to reduce the diameter of thewheels at the injection sites of dilutions of antibody which on all thecontrols have less than maximum response. Amounts of the compounds wereadministered to rats each amount to a test group of six animals at aspecified time prior to intravenous challenge with ovalbumin. Thediameters of the blue wheals which developed on the tests group ofanimals were compared with those on a control group of six animalstreated in the same way as the test group, but which had not receivedthe compound under test.

    % Inhibition of P.C.A. = 100 (1 - a/b)

a = The mean of the sum of the diameters of the wheals produced in thetest group of animals at those antibody sites where all the controlgroup of animals gave less than maximum response.

b = The mean of the sum of diameters of the wheals produced in thecontrol group of animals at those antibody sites where all the animalsin the group gave less than maximum response.

The preferred method of administration was a solution of the testcompound dissolved in pH 7.2 buffer and neutralised with sodiumbicarbonate. For those compounds having insoluble sodium salts, thesalts were isolated by reaction of the free nitro compound with 2.5Nsodium hydroxide and the filtered sodium salt washed free of alkali withwater. The dried salts were then administered as a suspension in 1%methyl cellulose.

    __________________________________________________________________________                              TIME BETWEEN                                                                  DOSING AND                                                                             % INHIBITION                               TEST      FORM IN WHICH                                                                           DOSE  CHALLENGE                                                                              OF                                         COMPOUND  ADMINISTERED                                                                            (mg/kg)                                                                             (MINS)   PCA RESPONSE                               __________________________________________________________________________    5-bromo-2-                                                                              Solution of Na                                                                          25    0        46                                         nitroindane-1,                                                                          salt      25    60       87                                         3-dione             100   0        30                                         3-dione             100   0        30                                                             100   60       64                                         5-methyl-2-                                                                             solution of Na                                                                          25    0        66                                         nitroindane-1,3-                                                                        salt      25    30       44                                         dione               100   0        100                                                            100   30       47                                         4-methyl- Suspension of                                                                           25    0        2                                          2-nitroindane-                                                                          Na salt in 1%                                                                           25    60       33                                         1,3-dione methyl    100   0        6                                                    cellulose 100   60       57                                         4-methoxy-2-                                                                            Suspension of                                                                           25    0        -2                                         nitroindane-1,                                                                          Na salt in                                                                              25    60       25                                         3-dione   1% methyl 100   0        18                                                   cellulose 100   60       36                                         2-nitro-  Suspension of                                                                           25    0        100                                        benz[f] indane-                                                                         Na salt in                                                                              25    60       37                                         1,3-dione 1% methyl 100   0        100                                                  cellulose 100   60       72                                         4-bromo-2-                                                                              Suspension of                                                                           25    0        8                                          nitroindane-                                                                            Na salt in 1%                                                                           25    60       24                                         1,3-dione methyl    100   0        -4                                                   cellulose 100   60       70                                         4,5,6,7-  Solution  25    0        -13                                        tetrachloro-                                                                            of Na     25    60       9                                          2-nitroin-                                                                              salt      10    0        -3                                         dane-1,3-           100   60       7                                          dione                                                                         4-ethoxy-2-                                                                             Solution of                                                                             25    0        13                                         nitroindane-                                                                            Na salt   25    30       68                                         1,3-dione           100   0        76                                                             100   30       55                                         4-fluoro-2-                                                                             Solution of                                                                             25    0        48                                         nitroindane-                                                                            Na salt   25    30       8                                          1,3-dione           100   0        86                                                             100   30       30                                         4-methoxy-7-                                                                            Solution of                                                                             25    0        34                                         methyl-2- Na salt   25    30       62                                         nitroindane-        100   0        36                                         1,3-dione           100   30       44                                         5,6-dimethyl-                                                                           Suspension of                                                                           25    0        92                                         2-nitroindane-                                                                          Na salt in                                                                              26    60       48                                         1,3-dione 1% methyl 100   0        73                                                   cellulose 100   60       54                                         4-isopropyloxy-                                                                         Suspension of                                                                           25    0        23                                         2-nitroindane-                                                                          Na salt in                                                                              25    30       36                                         1,3-dione 1% methyl 100   0        49                                                   cellulose 100   30       51                                         4,6-dimethyl-                                                                           Solution of                                                                             25    0        58                                         2-nitroindane-                                                                          Na salt   25    30       27                                         1,3-dione           10    0        69                                                             100   0        35                                         4,7-dimethyl-                                                                           Suspension of                                                                           25    0        35                                         2-nitroindane-                                                                          Na salt in                                                                              25    60       16                                         1,3-dione 1% methyl 100   0        46                                                   cellulose 100   60       8                                          2-nitrobenz(e)-                                                                         Suspension of                                                                           25    0        16                                         indane-1,3-                                                                             Na salt in                                                                              25    60       50                                         dione     1% methyl 10    0        13                                                   cellulose 100   60       47                                         4-ethyl-2-                                                                              Suspension of                                                                           25    0        -5                                         nitroindane-1,                                                                          Na salt in                                                                              25    60       23                                         3-dione   1% methyl 100   0        1                                                    cellulose 100   60       25                                         4-methoxy-6-                                                                            Solution of                                                                             25    0        34                                         methyl-2- Na salt   25    30       31                                         nitroindane-1       100   0        80                                         3-dione   100       30    24                                                  6-ethyl-4-                                                                              Solution  25    0        66                                         methoxy-2-                                                                              of Na     25    30       37                                         nitroindane-1,                                                                          Salt      100   0        91                                         3-dione             100   30       32                                         2-nitro 5-phenyl                                                                        Suspension                                                                              25    0        58                                         indane-   of Na salt                                                                              25    60       56                                         1,3-dione in 1%     100   0        82                                                   methyl    100   60       36                                                   cellulose                                                           4-isobutyloxy-                                                                          Solution  25    0        61                                         2-nitroindane-                                                                          of Na salt                                                                              25    30       28                                         1,3-dione           100   0        78                                                             100   30       41                                         4-n-butyloxy-                                                                           Solution  25    0        29                                         2-nitroindane-                                                                          of Na salt                                                                              25    60       43                                         1,3-dione           100   0        63                                                             100   60       50                                         2-nitro-4-                                                                              Solution  25    0        12                                         phenyl indane-                                                                          of Na     25    60       22                                         1,3 indione                                                                             Salt      100   0        8                                                              100   60       24                                         __________________________________________________________________________

EXAMPLE 25 a. 4,5-Cyclohexano indane-1,3-dione

The Claisen condensation of dimethyl tetraline 5,6-dicarboxylate (11.6g; 0.0465 mole) with ethyl acetate (15 ml.) as described in example 1b.,afforded 4,5-cyclohexano indane-1,3-dione as a yellow crystallinecompound, m.p. (benzene) 97°-99°C (Found: C, 77.80; H, 5.74; C₁₃ H₁₂ O₂requires: C, 77.98; H, 6.04).

b. 4,5-Cyclohexano-2-nitroindane-1,3-dione

To a stirred suspension of 4,5-cyclohexano indane-1,3-dione (1.0 g;0.005 mole) in anhydrous ether (8.0 ml.) at -20°C was added fumingnitric acid (1.0 ml.) dropwise. After stirring at 0°-5°C for 1 hr. andthen at room temperature for a further 1 hr. water (20 ml.) was added,the ether removed under vacuo and the solution filtered. Addition ofconcentrated hydrochloric acid to the clear, yellow filtrate affordedthe title compound on cooling, m.p. (water, hydrochloric acid)108°-109°C. (Found: C, 63.67; H, 4.48; N, 5.43; C₁₃ H₁₁ NO₄ requires: C,63.67; H, 4.52; N, 5.71%).

EXAMPLE 26

a. 4,5-Cyclopentano indane-1,3-dione

Condensation of dimethyl indane 4,5-dicarboxylate (12.42 g; 0.053 mole)with ethyl acetate as in example 1b gave the dione as a yellow solid,m.p. (benzene, petroleum [40°-60°]) 159°-162°(d). (Found: C, 77.55; H,5.65; C₁₂ H₁₀ O₂ requires: C, 77.40; H, 5.41%).

b. 4,5-Cyclopentano-2-nitro indane-1,3-dione

Fuming nitric acid (1.0 ml.) was added dropwise to a stirred suspensionof 4,5-cyclopentano indane-1,3-dione (0.95 g; 0.005 mole) in dry ether(8.0 ml.) at 5°-10°C and the mixture stirred at this temperature for 45mins. Further stirring at room temperature for 1 hr. followed byaddition of water (20 ml.), evaporation of ether, and filtration gave aclear, yellow filtrate. Addition of an equal volume of concentratedhydrochloric acid to the latter yielded the 2-nitro derivative as ayellow crystalline solid, m.p. (water, hydrochloric acid) 128°-130°C.(Found: C, 59.96; H, 3.96; N, 5.89: C₁₂ H₉ NO₄. 1/2 H₂ O requires: C,60.80; H, 4.20; N, 5.83%).

EXAMPLE 27

a. 5-Methoxy-6-Methyl indane-1,3-dione

A solution of dimethyl 4-methoxy-5-methyl phthalate (14.21 g; 0.06 mole;m.p. 66°-68°C) in ethyl acetate (20 ml.) was added to a 50% dispersionof sodium hydride in mineral oil (3.95 g; 0.082 mole of NaH) and themixture refluxed for 4 hrs. The orange-brown sodium salt which separatedwas broken-up with 1:1 ethanol, ether, filtered and dried in vacuo.Addition of the dried solid to hot (80°C) 5N hydrochloric acid (15 ml.)followed by stirring at 70°C for 7 mins. gave the title dione as ayellow solid, m.p. (benzene) 215°-216°C. (Found: C, 69.11; H, 5.50; C₁₁H₁₀ O₃ requires: C, 69.46; H, 5.30).

b. 5-Methoxy-6-methyl-2-nitro indane-1,3-dione

Nitration of 5-methoxy-6-methyl indane-1,3-dione as outlined in example1b gave the 2-nitro derivative as an initially yellow solid which turnedorange on dehydration, m.p. 110°C. (Found: C, 56.59; H, 3.83; H, 6.03:C₁₁ H₉ NO₅ requires: C, 56.17; H, 3.86; N, 5.96%).

    __________________________________________________________________________     Biological Data for Compounds not                                            included in Table I                                                           __________________________________________________________________________                              Time between                                                                  dosing and                                                                           % Inhibition                                           Form in which                                                                           dose  challenge                                                                            of PCA                                       Test Compound                                                                           administered.                                                                           (mg./kg.)                                                                           (mins).                                                                              response                                     __________________________________________________________________________    4-n-propyloxy                                                                           Solution of                                                                             25    0      77                                           2-nitroindane-                                                                          sodium salt                                                                             25    30     37                                           1,3-dione.          100   0      30                                                               100   30     37                                           4,5-cyclohexano                                                                         Suspension of                                                                           34    0      7                                            2-nitroindane-                                                                          Na salt in 1%                                                                           34    60     32                                           1,3-dione methyl cellulose                                                    4,5-cyclopentano                                                                        Suspension of Na                                                                        25    0      5                                            2-nitroindane-                                                                          salt in 1% methyl                                                                       25    60     34                                           1,3-dione cellulose 100   0      26                                                               100   60     28                                           __________________________________________________________________________

We claim:
 1. A pharmaceutical composition in a form suitable for oral,parenteral or insufflation administration to humans comprising an amountof a compound of the formula (I) ##SPC9##or apharmaceutically-acceptable nontoxic salt thereof, wherein R₁ and R₂, R₂and R₃ or R₃ and R₄ are alkyl or alkenyl joined to form a 5- or6-membered carbocyclic ring, sufficient to be effective for theprophylaxis of asthma, hayfever or rhinitis,in combination with apharmaceutically-acceptable, nontoxic, inert diluent or carrier suitablefor said administration form.
 2. A pharmaceutical composition accordingto claim 1 wherein the compound of formula (I) is in the form of thesodium salt.
 3. A pharmaceutical composition according to claim 1wherein R₁ and R₂ or R₂ and R₃ or R₃ and R₄ taken together with thecarbon atoms to which they are joined form a 1,2-phenylene,1,2-cyclohexylene or 1,2-cyclohexenylene ring.
 4. A pharmaceuticalcomposition according to claim 1 which is in the form of a microfinepowder for insufflation.
 5. A pharmaceutical composition according toclaim 4 wherein the microfine powder is such that substantially all theparticles have diameters of less than 50 microns.
 6. A pharmaceuticalcomposition according to claim 1 wherein the diluent or carrier is asterile liquid carrier suitable for injection.
 7. A pharmaceuticalcomposition according to claim 1 in the form of a pill, tablet, capsuleor powder suitable for mixing with water to form a syrup.
 8. Apharmaceutical composition according to claim 1 wherein the compound is2-nitro benz indane-1,3-dione.
 9. A pharmaceutical composition accordingto claim 1 wherein the compound is 2-nitro benz(e)indane-1,3-dione. 10.A pharmaceutical composition according to claim 1 wherein the compoundis 4,5-cyclohexane-2-nitroindane-1,3-dione.
 11. A pharmaceuticalcomposition according to claim 1 wherein the compound is4,5-cyclopentano-2-nitroindane-1,3-dione.
 12. A method for theprophylaxis of asthma, hayfever and rhinitis in humans which comprisesadministering to a human in need thereof orally, parenterally or byinsufflation an amount of a compound of the formula (I) ##SPC10##or apharmaceutically-acceptable, nontoxic salt thereof, wherein R₁ and R₂,R₂ and R₃ or R₃ and R₄ are alkyl or alkenyl joined to form a 5- or6-membered carbocyclic ring, sufficient to be effective for theprophylaxis of asthma, hayfever or rhinitis,in combination with apharmaceutically-acceptable, nontoxic, inert diluent or carrier suitablefor said administration form.
 13. a method according to claim 12 whereinthe compound of formula (I) is administered in the form of the sodiumsalt.
 14. A method according to claim 12 wherein R₁ and R₂ or R₂ and R₃or R₃ and R₄ taken together with the carbon atoms to which they arejoined form a 1,2-phenylene, 1,2-cyclohexylene or 1,2-cyclohexenylenering.
 15. A method according to claim 12 wherein the compound and thecarrier are in the form of a microfine powder and the administration isby insufflation.
 16. A method according to claim 12 wherein the compoundand the carrier are in the form of a microfine powder such thatsubstantially all the particles have diameters of less than 50 micronsand the administration is by insufflation.
 17. A method according toclaim 12 wherein the administration is oral.
 18. A method according toclaim 12 wherein the administration is parenteral.
 19. A methodaccording to claim 12 wherein the compound is 2-nitrobenzindane-1,3-dione.
 20. A method according to claim 12 wherein thecompound is 2-nitro benze(e)indane-1,3-dione.
 21. A method according toclaim 12 wherein the compound is4,5-cyclohexane-2-nitroindane-1,3-dione.
 22. A method according to claim12 wherein the compound is 4,5-cyclopentano-2-nitroindane-1,3-dione.